VCV000546975.44 - ClinVar

NM_032119.4(ADGRV1):c.3974C>T (p.Thr1325Met)

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.

(7)

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 pathogenic(1); Uncertain significance(5); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_032119.4(ADGRV1):c.3974C>T (p.Thr1325Met)

Variation ID: 546975 Accession: VCV000546975.44

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q14.3 5: 90653548 (GRCh38) [ NCBI UCSC ] 5: 89949365 (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 9, 2018	Oct 20, 2024	Jan 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_032119.4:c.3974C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_115495.3:p.Thr1325Met	missense
NR_003149.2:n.4073C>T		non-coding transcript variant
NC_000005.10:g.90653548C>T
NC_000005.9:g.89949365C>T
NG_007083.2:g.129205C>T
LRG_1095:g.129205C>T
LRG_1095t1:c.3974C>T	LRG_1095p1:p.Thr1325Met

... more HGVS ... less HGVS

Protein change

T1325M

Other names

Canonical SPDI

NC_000005.10:90653547: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 0.00004

Exome Aggregation Consortium (ExAC) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00006

The Genome Aggregation Database (gnomAD) 0.00007

Links

dbSNP: rs756414393 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.
ADGRV1		-	-	GRCh38 GRCh37	6331	6387

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	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jan 8, 2024	RCV000659018.30
Febrile seizures, familial, 4 Usher syndrome type 2C	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2018	RCV000764616.3
Usher syndrome type 2C	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001155124.5
Abnormal activity of mitochondrial respiratory chain	Likely pathogenic (1)	criteria provided, single submitter	Apr 12, 2021	RCV001375131.4
not specified	Uncertain significance (1)	criteria provided, single submitter	May 16, 2023	RCV002282295.3
ADGRV1-related disorder	Uncertain significance (1)	criteria provided, single submitter	Jan 19, 2023	RCV004547830.1

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 (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Febrile seizures, familial, 4 Usher syndrome type 2C Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000895723.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Usher syndrome type 2C Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001316533.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 25333064 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely pathogenic (Apr 12, 2021)	criteria provided, single submitter (ClinGen HL ACMG Specifications v1) Method: clinical testing	Abnormal activity of mitochondrial respiratory chain Affected status: yes Allele origin: germline	Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center Accession: SCV001572092.2 First in ClinVar: Apr 29, 2021 Last updated: Apr 29, 2021	Publications: PubMed (1) PubMed: 25333064 Comment: PS1_Strong, PM2_Moderate, PP3_Supporting Testing laboratory: CeGaT Praxis fuer Humangenetik Tuebingen
Uncertain significance (May 16, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002570965.2 First in ClinVar: Sep 17, 2022 Last updated: Jun 24, 2023	Publications: PubMed (1) PubMed: 25333064 Comment: Variant summary: ADGRV1 c.3974C>T (p.Thr1325Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more) Variant summary: ADGRV1 c.3974C>T (p.Thr1325Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 248924 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ADGRV1 causing Usher Syndrome (4.4e-05 vs 0.0054), allowing no conclusion about variant significance. c.3974C>T has been reported in the literature as a non-informative genotype (second allele/genotype not specified) in at-least one individual affected with features of Usher Syndrome (example, Krawitz_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25333064). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Jan 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ADGRV1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004113906.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The ADGRV1 c.3974C>T variant is predicted to result in the amino acid substitution p.Thr1325Met. This variant was reported in an individual with Usher syndrome (Krawitz … (more) The ADGRV1 c.3974C>T variant is predicted to result in the amino acid substitution p.Thr1325Met. This variant was reported in an individual with Usher syndrome (Krawitz et al 2014. PubMed ID: 25333064). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-89949365-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Likely benign (Jan 08, 2024)	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: SCV001202716.4 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024
Uncertain significance (Jul 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000780821.29 First in ClinVar: Jul 09, 2018 Last updated: Oct 20, 2024	Number of individuals with the variant: 3

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

Variant summary: ADGRV1 c.3974C>T (p.Thr1325Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 248924 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ADGRV1 causing Usher Syndrome (4.4e-05 vs 0.0054), allowing no conclusion about variant significance. c.3974C>T has been reported in the literature as a non-informative genotype (second allele/genotype not specified) in at-least one individual affected with features of Usher Syndrome (example, Krawitz_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25333064). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

The ADGRV1 c.3974C>T variant is predicted to result in the amino acid substitution p.Thr1325Met. This variant was reported in an individual with Usher syndrome (Krawitz et al 2014. PubMed ID: 25333064). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-89949365-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Screening for single nucleotide variants, small indels and exon deletions with a next-generation sequencing based gene panel approach for Usher syndrome.	Krawitz PM	Molecular genetics & genomic medicine	2014	PMID: 25333064

Text-mined citations for rs756414393 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_032119.4(ADGRV1):c.3974C>T (p.Thr1325Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs756414393 ...