VCV000556881.9 - ClinVar

NM_000260.4(MYO7A):c.1997G>A (p.Arg666Gln)

Germline

Top reviewed classifications are shown here.

Submission summary:

6 submissions

6 submitters

5 conditions

Reviewed by expert panel

Uncertain significance

May 2020 by ClinGen Hearin… FDA Recognized Database

for Usher syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000260.4(MYO7A):c.1997G>A (p.Arg666Gln)

Variation ID: 556881 Accession: VCV000556881.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q13.5 11: 77174817 (GRCh38) [ NCBI UCSC ] 11: 76885863 (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	Aug 5, 2018	Apr 6, 2024	May 20, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_000260.4(MYO7A):c.1997G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000260.4:c.1997G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000251.3:p.Arg666Gln	missense
NM_001127180.2:c.1997G>A	NP_001120652.1:p.Arg666Gln	missense
NM_001369365.1:c.1964G>A	NP_001356294.1:p.Arg655Gln	missense
NC_000011.10:g.77174817G>A
NC_000011.9:g.76885863G>A
NG_009086.2:g.51572G>A
LRG_1420:g.51572G>A
LRG_1420t1:c.1997G>A	LRG_1420p1:p.Arg666Gln

... more HGVS ... less HGVS

Protein change

R666Q, R655Q

Other names

Canonical SPDI

NC_000011.10:77174816:G: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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00006

The Genome Aggregation Database (gnomAD) 0.00009

Links

dbSNP: rs782396605 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.
MYO7A		-	-	GRCh38 GRCh37	4328	4339

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.
Autosomal recessive nonsyndromic hearing loss 2 Usher syndrome type 1	Uncertain significance (1)	criteria provided, single submitter	Feb 28, 2018	RCV000672944.1
Usher syndrome type 1	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 25, 2024	RCV000988605.6
not provided	Uncertain significance (1)	criteria provided, single submitter	Sep 13, 2022	RCV001309116.3
Usher syndrome	Uncertain significance (1)	reviewed by expert panel	May 20, 2020	RCV001171540.1
Usher syndrome type 1B	Uncertain significance (1)	no assertion criteria provided	Jan 16, 2020	RCV001830456.1

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 (May 20, 2020)	reviewed by expert panel (ClinGen HL ACMG Specifications v1) Method: curation	Usher syndrome (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	ClinGen Hearing Loss Variant Curation Expert Panel FDA Recognized Database Accession: SCV001334325.1 First in ClinVar: Jun 07, 2020 Last updated: Jun 07, 2020	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4923dcaa-6018-41a1-b68f-39af89d9e3cf Comment: The c.1997G>A (p.Arg666Gln) variant in MYO7A is present in 10/42046 (0.012% CI 95%) of African alleles in gnomAD v3, which is a low enough frequency … (more) The c.1997G>A (p.Arg666Gln) variant in MYO7A is present in 10/42046 (0.012% CI 95%) of African alleles in gnomAD v3, which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). This variant has been detected in 1 proband with Usher syndrome, however, they carried another VUS with phase unknown (PM3_Supporting not met; ClinVar ID: 196099; PMIDs: 27460420, 31479088). The REVEL computational prediction analysis tool produced a score of 0.841, which is above the threshold necessary to apply PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PP3. (less)
Uncertain significance (Feb 28, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Usher syndrome type 1 Autosomal recessive nonsyndromic hearing loss 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000798101.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (2) PubMed: 27460420‚ 27344577
Uncertain significance (Sep 13, 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: SCV001498602.2 First in ClinVar: Mar 07, 2021 Last updated: Mar 26, 2023	Publications: PubMed (4) PubMed: 27344577‚ 27460420‚ 31479088‚ 33297549 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 666 of the MYO7A protein (p.Arg666Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 666 of the MYO7A protein (p.Arg666Gln). This variant is present in population databases (rs782396605, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome, deafness (PMID: 27344577, 27460420, 31479088, 33297549). ClinVar contains an entry for this variant (Variation ID: 556881). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO7A 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 (Apr 21, 2023)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Usher syndrome type 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001138384.3 First in ClinVar: Jan 09, 2020 Last updated: Apr 23, 2023
Uncertain significance (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 1 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806302.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Uncertain significance (Jan 16, 2020)	no assertion criteria provided Method: clinical testing	Usher syndrome type 1B Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002086597.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Comment:

The c.1997G>A (p.Arg666Gln) variant in MYO7A is present in 10/42046 (0.012% CI 95%) of African alleles in gnomAD v3, which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). This variant has been detected in 1 proband with Usher syndrome, however, they carried another VUS with phase unknown (PM3_Supporting not met; ClinVar ID: 196099; PMIDs: 27460420, 31479088). The REVEL computational prediction analysis tool produced a score of 0.841, which is above the threshold necessary to apply PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PP3.

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 666 of the MYO7A protein (p.Arg666Gln). This variant is present in population databases (rs782396605, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome, deafness (PMID: 27344577, 27460420, 31479088, 33297549). ClinVar contains an entry for this variant (Variation ID: 556881). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO7A 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.

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
Improving the Management of Patients with Hearing Loss by the Implementation of an NGS Panel in Clinical Practice.	García-García G	Genes	2020	PMID: 33297549
PHENOTYPIC CHARACTERISTICS OF ROD-CONE DYSTROPHY ASSOCIATED WITH MYO7A MUTATIONS IN A LARGE FRENCH COHORT.	Khateb S	Retina (Philadelphia, Pa.)	2020	PMID: 31479088
An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients.	Bonnet C	European journal of human genetics : EJHG	2016	PMID: 27460420
Spectrum of DNA variants for non-syndromic deafness in a large cohort from multiple continents.	Yan D	Human genetics	2016	PMID: 27344577
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4923dcaa-6018-41a1-b68f-39af89d9e3cf	-	-	-	-

Text-mined citations for rs782396605 ...

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_000260.4(MYO7A):c.1997G>A (p.Arg666Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs782396605 ...