VCV000245964.33 - ClinVar

NM_170707.4(LMNA):c.1487C>T (p.Thr496Met)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(24)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely risk allele(1); Uncertain significance(19)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_170707.4(LMNA):c.1487C>T (p.Thr496Met)

Variation ID: 245964 Accession: VCV000245964.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 156137027 (GRCh38) [ NCBI UCSC ] 1: 156106818 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 25, 2016	May 1, 2024	Feb 21, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_170707.4:c.1487C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_733821.1:p.Thr496Met	missense
NM_005572.4:c.1487C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005563.1:p.Thr496Met	missense
NM_001257374.3:c.1151C>T	NP_001244303.1:p.Thr384Met	missense
NM_001282624.2:c.1244C>T	NP_001269553.1:p.Thr415Met	missense
NM_001282625.2:c.1487C>T	NP_001269554.1:p.Thr496Met	missense
NM_001282626.2:c.1487C>T	NP_001269555.1:p.Thr496Met	missense
NM_170708.4:c.1487C>T	NP_733822.1:p.Thr496Met	missense
NC_000001.11:g.156137027C>T
NC_000001.10:g.156106818C>T
NG_008692.2:g.59455C>T
LRG_254:g.59455C>T
LRG_254t1:c.1487C>T	LRG_254p1:p.Thr496Met
LRG_254t2:c.1487C>T

... more HGVS ... less HGVS

Protein change

T496M, T384M, T415M

Other names

Canonical SPDI

NC_000001.11:156137026:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00002

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA050321 dbSNP: rs200466188 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LMNA		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1845	2125

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (6)	criteria provided, multiple submitters, no conflicts	Jul 16, 2019	RCV000235878.10
Charcot-Marie-Tooth disease type 2B1 Congenital muscular dystrophy due to LMNA mutation Dilated cardiomyopathy 1A Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome Emery-Dreifuss muscular dystrophy 2, autosomal dominant Emery-Dreifuss muscular dystrophy 3, autosomal recessive Familial partial lipodystrophy, Dunnigan type Heart-hand syndrome, Slovenian type Hutchinson-Gilford syndrome Lethal tight skin contracture syndrome Mandibuloacral dysplasia with type A lipodystrophy	Uncertain significance (1)	criteria provided, single submitter	Apr 10, 2018	RCV000681642.5
Charcot-Marie-Tooth disease type 2	Uncertain significance (1)	criteria provided, single submitter	Dec 23, 2023	RCV000653862.7
Hutchinson-Gilford syndrome	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001100889.4
Charcot-Marie-Tooth disease type 2B1	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001100619.4
Emery-Dreifuss muscular dystrophy	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001098789.4
Congenital muscular dystrophy due to LMNA mutation	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001100613.4
Mandibuloacral dysplasia with type A lipodystrophy	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001100618.4
Lethal tight skin contracture syndrome	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001100620.4
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jul 31, 2023	RCV001180056.4
Familial partial lipodystrophy, Dunnigan type	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001100614.4
Emery-Dreifuss muscular dystrophy 2, autosomal dominant	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001100615.4
Dilated cardiomyopathy 1A	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Feb 21, 2024	RCV001100616.9
Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001100617.4
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Feb 10, 2021	RCV002392729.2
Charcot-Marie-Tooth disease type 2B1 Congenital muscular dystrophy due to LMNA mutation Dilated cardiomyopathy 1A Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome Emery-Dreifuss muscular dystrophy 2, autosomal dominant Emery-Dreifuss muscular dystrophy 3, autosomal recessive Familial partial lipodystrophy, Dunnigan type Heart-hand syndrome, Slovenian type Hutchinson-Gilford syndrome Mandibuloacral dysplasia with type A lipodystrophy Restrictive dermopathy 2	Uncertain significance (1)	criteria provided, single submitter	May 16, 2022	RCV002494678.1
Primary dilated cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Nov 20, 2023	RCV003998908.2
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Oct 12, 2015)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000293193.10 First in ClinVar: Jul 25, 2016 Last updated: Jul 25, 2016	Comment: The T496M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T496M … (more) The T496M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T496M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T496M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (L489P, W498R, W498C) have been reported in the Human Gene Mutation Database in association with LMNA-associated disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. (less)
Uncertain significance (Apr 10, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Restrictive dermopathy 1 Emery-Dreifuss muscular dystrophy 2, autosomal dominant Congenital muscular dystrophy due to LMNA mutation Mandibuloacral dysplasia with type A lipodystrophy Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome Familial partial lipodystrophy, Dunnigan type Hutchinson-Gilford syndrome Heart-hand syndrome, Slovenian type Emery-Dreifuss muscular dystrophy 3, autosomal recessive Emery-Dreifuss muscular dystrophy 2, autosomal dominant Charcot-Marie-Tooth disease type 2B1 Dilated cardiomyopathy 1A Affected status: unknown Allele origin: maternal	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000809088.1 First in ClinVar: Sep 30, 2018 Last updated: Sep 30, 2018
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Emery-Dreifuss muscular dystrophy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001255177.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Congenital muscular dystrophy due to LMNA mutation Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001257141.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Familial partial lipodystrophy, Dunnigan type Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001257142.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Emery-Dreifuss muscular dystrophy 2, autosomal dominant Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001257143.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Dilated cardiomyopathy 1A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001257144.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001257145.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Mandibuloacral dysplasia with type A lipodystrophy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001257146.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Charcot-Marie-Tooth disease type 2B1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001257147.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Restrictive dermopathy 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001257148.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hutchinson-Gilford syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001257435.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jun 03, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1A Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001522188.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (May 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1A Familial partial lipodystrophy, Dunnigan type Hutchinson-Gilford syndrome Emery-Dreifuss muscular dystrophy 2, autosomal dominant Emery-Dreifuss muscular dystrophy 2, autosomal dominant Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome Mandibuloacral dysplasia with type A lipodystrophy Charcot-Marie-Tooth disease type 2B1 Heart-hand syndrome, Slovenian type Congenital muscular dystrophy due to LMNA mutation Emery-Dreifuss muscular dystrophy 3, autosomal recessive Restrictive dermopathy 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002803921.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Jul 16, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003814681.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Jul 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001344905.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 30847666 Comment: This missense variant replaces threonine with methionine at codon 496 of the LMNA protein. Computational prediction suggests that this variant may have a deleterious impact … (more) This missense variant replaces threonine with methionine at codon 496 of the LMNA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmia (PMID: 30847666). This variant has been identified in 4/251304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Dec 23, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000775752.6 First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 30847666 Comment: This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 496 of the LMNA protein (p.Thr496Met). … (more) This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 496 of the LMNA protein (p.Thr496Met). This variant is present in population databases (rs200466188, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 245964). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Likely risk allele (Feb 21, 2024)	criteria provided, single submitter (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1) Method: research	Dilated cardiomyopathy 1A (Autosomal dominant inheritance) Affected status: unknown Allele origin: unknown	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV003928188.2 First in ClinVar: Jun 17, 2023 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 23702046‚ 12628721‚ 17334235 Comment: Potent mutations in LMNA gene can lead to structural alteration in skeletal and cardiac muscle by altering the structure of Lamin A and Lamin C. … (more) Potent mutations in LMNA gene can lead to structural alteration in skeletal and cardiac muscle by altering the structure of Lamin A and Lamin C. It is associated with dilated cardiomyopathy and skeletal muscle dystrophies. However no sufficient evidence is found to ascertain the role of this particular variant rs200466188, yet.This variant is a potent moderate impact, deleterious variant with a CADD score of 33. This gene is found to be frequently associated with Dilated cardiomyopathy cases as per recent evidence as well with sufficient scientific evidence to support the reported classification. (less)
Uncertain Significance (Nov 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary dilated cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004815863.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Comment: This missense variant replaces threonine with methionine at codon 496 of the lamin A/C protein. Computational prediction suggests that this variant may have deleterious impact … (more) This missense variant replaces threonine with methionine at codon 496 of the lamin A/C protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/251304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 5
Uncertain significance (Feb 10, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002700855.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 30847666 Comment: The p.T496M variant (also known as c.1487C>T), located in coding exon 8 of the LMNA gene, results from a C to T substitution at nucleotide … (more) The p.T496M variant (also known as c.1487C>T), located in coding exon 8 of the LMNA gene, results from a C to T substitution at nucleotide position 1487. The threonine at codon 496 is replaced by methionine, an amino acid with similar properties. This variant has been detected in an individual reported to have arrhythmia; however, details were not provided (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Dec 01, 2015)	no assertion criteria provided Method: provider interpretation	not provided Affected status: unknown Allele origin: germline	Stanford Center for Inherited Cardiovascular Disease, Stanford University Accession: SCV000925153.1 First in ClinVar: Jul 01, 2019 Last updated: Jul 01, 2019
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001799285.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001917569.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001951793.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

The T496M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T496M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T496M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (L489P, W498R, W498C) have been reported in the Human Gene Mutation Database in association with LMNA-associated disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This missense variant replaces threonine with methionine at codon 496 of the LMNA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmia (PMID: 30847666). This variant has been identified in 4/251304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 496 of the LMNA protein (p.Thr496Met). This variant is present in population databases (rs200466188, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 245964). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Potent mutations in LMNA gene can lead to structural alteration in skeletal and cardiac muscle by altering the structure of Lamin A and Lamin C. It is associated with dilated cardiomyopathy and skeletal muscle dystrophies. However no sufficient evidence is found to ascertain the role of this particular variant rs200466188, yet.This variant is a potent moderate impact, deleterious variant with a CADD score of 33. This gene is found to be frequently associated with Dilated cardiomyopathy cases as per recent evidence as well with sufficient scientific evidence to support the reported classification.

Comment:

This missense variant replaces threonine with methionine at codon 496 of the lamin A/C protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/251304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

The p.T496M variant (also known as c.1487C>T), located in coding exon 8 of the LMNA gene, results from a C to T substitution at nucleotide position 1487. The threonine at codon 496 is replaced by methionine, an amino acid with similar properties. This variant has been detected in an individual reported to have arrhythmia; however, details were not provided (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.	van Lint FHM	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2019	PMID: 30847666
LMNA mutations in Polish patients with dilated cardiomyopathy: prevalence, clinical characteristics, and in vitro studies.	Saj M	BMC medical genetics	2013	PMID: 23702046
Lamin A/C mutations associated with familial and sporadic cases of dilated cardiomyopathy in Koreans.	Song K	Experimental & molecular medicine	2007	PMID: 17334235
Natural history of dilated cardiomyopathy due to lamin A/C gene mutations.	Taylor MR	Journal of the American College of Cardiology	2003	PMID: 12628721

Text-mined citations for rs200466188 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_170707.4(LMNA):c.1487C>T (p.Thr496Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200466188 ...