VCV000594359.24 - ClinVar

NM_005529.7(HSPG2):c.11863G>T (p.Val3955Leu)

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.

(11)

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_005529.7(HSPG2):c.11863G>T (p.Val3955Leu)

Variation ID: 594359 Accession: VCV000594359.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.12 1: 21829512 (GRCh38) [ NCBI UCSC ] 1: 22156005 (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	Dec 16, 2018	Oct 8, 2024	May 29, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005529.7:c.11863G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005520.4:p.Val3955Leu	missense
NM_001291860.2:c.11866G>T	NP_001278789.1:p.Val3956Leu	missense
NC_000001.11:g.21829512C>A
NC_000001.10:g.22156005C>A
NG_016740.1:g.112746G>T

... more HGVS ... less HGVS

Protein change

V3955L, V3956L

Other names

Canonical SPDI

NC_000001.11:21829511:C:A

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) 0.00022

Links

dbSNP: rs145155624 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.
HSPG2		-	-	GRCh38 GRCh37	2553	2856

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 (5)	criteria provided, multiple submitters, no conflicts	May 29, 2023	RCV000729627.13
not specified	Uncertain significance (1)	criteria provided, single submitter	Aug 22, 2018	RCV001002036.8
Lethal Kniest-like syndrome	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001097837.4
Schwartz-Jampel syndrome	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001097836.4
Lethal Kniest-like syndrome Schwartz-Jampel syndrome type 1	not provided (1)	no classification provided	-	RCV001824872.2
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Apr 13, 2022	RCV002533109.2
HSPG2-related disorder	Uncertain significance (1)	no assertion criteria provided	Dec 20, 2023	RCV004540045.2

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 23, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000857303.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HSPG2 Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Nov 05, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001144144.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020
Uncertain significance (Aug 22, 2018)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001159860.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020	Comment: The HSPG2 c.11863G>T; p.Val3955Leu variant (rs145155624), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in … (more) The HSPG2 c.11863G>T; p.Val3955Leu variant (rs145155624), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in the non-Finnish European population with an overall allele frequency of 0.029% (36/125814 alleles) in the Genome Aggregation Database. The valine at codon 3955 is weakly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Val3955Leu variant is uncertain at this time. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Schwartz-Jampel syndrome type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001254154.1 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	Lethal Kniest-like syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001254155.1 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 (Aug 16, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002214820.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Comment: This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3955 of the HSPG2 protein (p.Val3955Leu). … (more) This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3955 of the HSPG2 protein (p.Val3955Leu). This variant is present in population databases (rs145155624, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with HSPG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 594359). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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)
Uncertain significance (May 29, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003927554.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Uncertain significance (Aug 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003811922.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Apr 13, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003690843.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.11863G>T (p.V3955L) alteration is located in exon 86 (coding exon 86) of the HSPG2 gene. This alteration results from a G to T substitution … (more) The c.11863G>T (p.V3955L) alteration is located in exon 86 (coding exon 86) of the HSPG2 gene. This alteration results from a G to T substitution at nucleotide position 11863, causing the valine (V) at amino acid position 3955 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Dec 20, 2023)	no assertion criteria provided Method: clinical testing	HSPG2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004793913.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The HSPG2 c.11863G>T variant is predicted to result in the amino acid substitution p.Val3955Leu. To our knowledge, this variant has not been reported in the … (more) The HSPG2 c.11863G>T variant is predicted to result in the amino acid substitution p.Val3955Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-22156005-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
not provided (-)	no classification provided Method: phenotyping only	Lethal Kniest-like syndrome Schwartz-Jampel syndrome type 1 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: paternal	GenomeConnect, ClinGen Accession: SCV002075209.2 First in ClinVar: Feb 12, 2022 Last updated: Jun 17, 2024	Comment: Variant interpreted as Uncertain significance and reported on 07-21-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the … (more) Variant interpreted as Uncertain significance and reported on 07-21-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Pregnancy history (present) , Maternal teratogenic exposure (present) , Overgrowth (present) , Hemihypertrophy (present) , Short stature (present) , Failure to thrive (present) , Decreased … (more) Pregnancy history (present) , Maternal teratogenic exposure (present) , Overgrowth (present) , Hemihypertrophy (present) , Short stature (present) , Failure to thrive (present) , Decreased response to growth hormone stimulation test (present) , Ear malformation (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , EEG abnormality (present) , Hypertonia (present) , Generalized hypotonia (present) , Movement disorder (present) , Autistic behavior (present) , Abnormal aggressive, impulsive or violent behavior (present) , Anxiety (present) , Compulsive behaviors (present) , Hyperpigmentation of the skin (present) , Abnormal limb bone morphology (present) , Joint hypermobility (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormal pattern of respiration (present) , Abnormality of the upper respiratory tract (present) , Abnormal large intestine morphology (present) , Abnormal renal morphology (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: female Testing laboratory: GeneDx Date variant was reported to submitter: 2021-07-21 Testing laboratory interpretation: Uncertain significance
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Comment:

The HSPG2 c.11863G>T; p.Val3955Leu variant (rs145155624), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in the non-Finnish European population with an overall allele frequency of 0.029% (36/125814 alleles) in the Genome Aggregation Database. The valine at codon 3955 is weakly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Val3955Leu variant is uncertain at this time.

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 sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3955 of the HSPG2 protein (p.Val3955Leu). This variant is present in population databases (rs145155624, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with HSPG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 594359). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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:

The c.11863G>T (p.V3955L) alteration is located in exon 86 (coding exon 86) of the HSPG2 gene. This alteration results from a G to T substitution at nucleotide position 11863, causing the valine (V) at amino acid position 3955 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

The HSPG2 c.11863G>T variant is predicted to result in the amino acid substitution p.Val3955Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-22156005-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

Variant interpreted as Uncertain significance and reported on 07-21-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HSPG2	-	-	-	-

Text-mined citations for rs145155624 ...

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 Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_005529.7(HSPG2):c.11863G>T (p.Val3955Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs145155624 ...