VCV000940483.11 - ClinVar

NM_001723.7(DST):c.3886A>G (p.Lys1296Glu)

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.

(3)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001723.7(DST):c.3886A>G (p.Lys1296Glu)

Variation ID: 940483 Accession: VCV000940483.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p12.1 6: 56620148 (GRCh38) [ NCBI UCSC ] 6: 56484946 (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 16, 2020	Aug 18, 2024	Jul 5, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001374736.1:c.4929+4382A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001723.7:c.3886A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001714.1:p.Lys1296Glu	missense
NM_001144769.5:c.4830+4382A>G		intron variant
NM_001144770.2:c.4416+4382A>G		intron variant
NM_001374722.1:c.4929+4382A>G		intron variant
NM_001374729.1:c.4296+4382A>G		intron variant
NM_001374730.1:c.4296+4382A>G		intron variant
NM_001374734.1:c.4956+4382A>G		intron variant
NM_001386100.1:c.4296+4382A>G		intron variant
NM_015548.5:c.3318+4382A>G		intron variant
NM_183380.4:c.4296+4382A>G		intron variant
NC_000006.12:g.56620148T>C
NC_000006.11:g.56484946T>C
NG_029322.2:g.339481A>G

... more HGVS ... less HGVS

Protein change

K1296E

Other names

Canonical SPDI

NC_000006.12:56620147:T:C

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

Exome Aggregation Consortium (ExAC) 0.00005

The Genome Aggregation Database (gnomAD), exomes 0.00007

Links

dbSNP: rs771246306 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.
DST		-	-	GRCh38	3746	3828

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.
Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency Hereditary sensory and autonomic neuropathy type 6	Uncertain significance (1)	criteria provided, single submitter	Jul 5, 2022	RCV001210079.8
Hereditary sensory and autonomic neuropathy type 6	Uncertain significance (1)	criteria provided, single submitter	Apr 30, 2021	RCV001727846.1
not provided	Uncertain significance (1)	criteria provided, single submitter	-	RCV004695181.1

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 (Apr 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary sensory and autonomic neuropathy type 6 (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Breda Genetics srl Accession: SCV001976517.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021	Comment: Based on allele frequency, in-silico prediction scores and a certain overlap with the clinical phenotype, we interpreted this variant at least as of uncertain significance. … (more) Based on allele frequency, in-silico prediction scores and a certain overlap with the clinical phenotype, we interpreted this variant at least as of uncertain significance. The lack of one or more of the following features has discouraged further investigations: lack of a possible second hit in autosomal recessive conditions, presence of healthy controls in databases for autosomal dominant conditions, presence of unmatching cardinal clinical features in the patient or in the known gene-disease association, and/or variant type outside the known gene mutational spectrum. (less)
Uncertain significance (Jul 05, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency Hereditary sensory and autonomic neuropathy type 6 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001381545.6 First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024	Comment: This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1296 of the DST protein … (more) This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1296 of the DST protein (p.Lys1296Glu). This variant is present in population databases (rs771246306, gnomAD 0.02%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 940483). This variant has not been reported in the literature in individuals affected with DST-related conditions. (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005189080.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024

Comment:

Based on allele frequency, in-silico prediction scores and a certain overlap with the clinical phenotype, we interpreted this variant at least as of uncertain significance. The lack of one or more of the following features has discouraged further investigations: lack of a possible second hit in autosomal recessive conditions, presence of healthy controls in databases for autosomal dominant conditions, presence of unmatching cardinal clinical features in the patient or in the known gene-disease association, and/or variant type outside the known gene mutational spectrum.

Comment:

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1296 of the DST protein (p.Lys1296Glu). This variant is present in population databases (rs771246306, gnomAD 0.02%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 940483). This variant has not been reported in the literature in individuals affected with DST-related conditions.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs771246306 ...

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_001723.7(DST):c.3886A>G (p.Lys1296Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs771246306 ...