The variant was co-segregated with Deafness, autosomal dominant 11 in multiple affected family members with additional meioses meeting moderate evidence levels (PMID: 15300860, PP1_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15300860, PS3_S). A different missense change at the same codon has been reported to be associated with MYO7A related disorder (ClinVar ID: VCV000043186, PMID:26969326, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.801, 3CNET: 0.926, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_000260.4(MYO7A):c.2557C>T (p.Arg853Cys)
Germline
Classification
Help
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.
(5)
Help
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.
Pathogenic/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000260.4(MYO7A):c.2557C>T (p.Arg853Cys)
Variation ID: 1333565 Accession: VCV001333565.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q13.5 11: 77179924 (GRCh38) [ NCBI UCSC ] 11: 76890970 (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 Jan 15, 2022 Aug 11, 2024 May 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000260.4:c.2557C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000251.3:p.Arg853Cys missense NM_000260.3:c.2557C>T NM_001127180.2:c.2557C>T NP_001120652.1:p.Arg853Cys missense NM_001369365.1:c.2524C>T NP_001356294.1:p.Arg842Cys missense NC_000011.10:g.77179924C>T NC_000011.9:g.76890970C>T NG_009086.2:g.56679C>T LRG_1420:g.56679C>T LRG_1420t1:c.2557C>T LRG_1420p1:p.Arg853Cys - Protein change
- R842C, R853C
- Other names
- -
- Canonical SPDI
- NC_000011.10:77179923:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
4324 | 4335 | |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 1, 2024 | RCV001808253.4 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 15, 2023 | RCV002541470.4 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nonsyndromic hearing loss 11
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058884.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant was co-segregated with Deafness, autosomal dominant 11 in multiple affected family members with additional meioses meeting moderate evidence levels (PMID: 15300860, PP1_M). Functional … (more)
The variant was co-segregated with Deafness, autosomal dominant 11 in multiple affected family members with additional meioses meeting moderate evidence levels (PMID: 15300860, PP1_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15300860, PS3_S). A different missense change at the same codon has been reported to be associated with MYO7A related disorder (ClinVar ID: VCV000043186, PMID:26969326, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.801, 3CNET: 0.926, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hearing impairment (present)
|
|
|
Pathogenic
(Nov 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nonsyndromic hearing loss 11
Affected status: yes
Allele origin:
germline
|
The Shared Resource Centre "Genome", Research Centre for Medical Genetics
Accession: SCV002756445.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(May 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004028400.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
A different missense change at this residue (p.(R853H)) has been reported as pathogenic in the published literature and at GeneDx in association with autosomal dominant … (more)
A different missense change at this residue (p.(R853H)) has been reported as pathogenic in the published literature and at GeneDx in association with autosomal dominant nonsyndromic hearing loss (Sloan-Heggen et al., 2016; Yamamoto et al., 2020; Cruz Marino et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15300860, 26969326, 32097363, 34387732) (less)
|
|
|
Pathogenic
(Oct 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003439856.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 853 of the MYO7A protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 853 of the MYO7A protein (p.Arg853Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 15300860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1333565). 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) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function. Experimental studies have shown that this missense change affects MYO7A function (PMID: 15300860). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nonsyndromic hearing loss 11
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005184387.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
Variant summary: MYO7A c.2557C>T (p.Arg853Cys) 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: MYO7A c.2557C>T (p.Arg853Cys) 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 was absent in 1531882 control chromosomes (gnomAD v4.1). c.2557C>T has been reported in the literature in multiple individuals affected with Autosomal Dominant Nonsyndromic Hearing Loss 11 (e.g. Bolz_2004, Shatokhina_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant disrupts Ca2+/CaM-dependent vasoconstriction (Bolz_2004). The following publications have been ascertained in the context of this evaluation (PMID: 15300860, 36555390). ClinVar contains an entry for this variant (Variation ID: 1333565). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
Comment:
Comment:
A different missense change at this residue (p.(R853H)) has been reported as pathogenic in the published literature and at GeneDx in association with autosomal dominant nonsyndromic hearing loss (Sloan-Heggen et al., 2016; Yamamoto et al., 2020; Cruz Marino et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15300860, 26969326, 32097363, 34387732)
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 853 of the MYO7A protein (p.Arg853Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 15300860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1333565). 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) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function. Experimental studies have shown that this missense change affects MYO7A function (PMID: 15300860). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: MYO7A c.2557C>T (p.Arg853Cys) 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 was absent in 1531882 control chromosomes (gnomAD v4.1). c.2557C>T has been reported in the literature in multiple individuals affected with Autosomal Dominant Nonsyndromic Hearing Loss 11 (e.g. Bolz_2004, Shatokhina_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant disrupts Ca2+/CaM-dependent vasoconstriction (Bolz_2004). The following publications have been ascertained in the context of this evaluation (PMID: 15300860, 36555390). ClinVar contains an entry for this variant (Variation ID: 1333565). Based on the evidence outlined above, the variant was classified as pathogenic.
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:
The variant was co-segregated with Deafness, autosomal dominant 11 in multiple affected family members with additional meioses meeting moderate evidence levels (PMID: 15300860, PP1_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15300860, PS3_S). A different missense change at the same codon has been reported to be associated with MYO7A related disorder (ClinVar ID: VCV000043186, PMID:26969326, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.801, 3CNET: 0.926, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
A different missense change at this residue (p.(R853H)) has been reported as pathogenic in the published literature and at GeneDx in association with autosomal dominant nonsyndromic hearing loss (Sloan-Heggen et al., 2016; Yamamoto et al., 2020; Cruz Marino et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15300860, 26969326, 32097363, 34387732)
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 853 of the MYO7A protein (p.Arg853Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 15300860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1333565). 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) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function. Experimental studies have shown that this missense change affects MYO7A function (PMID: 15300860). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: MYO7A c.2557C>T (p.Arg853Cys) 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 was absent in 1531882 control chromosomes (gnomAD v4.1). c.2557C>T has been reported in the literature in multiple individuals affected with Autosomal Dominant Nonsyndromic Hearing Loss 11 (e.g. Bolz_2004, Shatokhina_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant disrupts Ca2+/CaM-dependent vasoconstriction (Bolz_2004). The following publications have been ascertained in the context of this evaluation (PMID: 15300860, 36555390). ClinVar contains an entry for this variant (Variation ID: 1333565). Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Spectrum of Genes for Non-GJB2-Related Non-Syndromic Hearing Loss in the Russian Population Revealed by a Targeted Deafness Gene Panel. | Shatokhina O | International journal of molecular sciences | 2022 | PMID: 36555390 |
| Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. | Sloan-Heggen CM | Human genetics | 2016 | PMID: 26969326 |
| Impaired calmodulin binding of myosin-7A causes autosomal dominant hearing loss (DFNA11). | Bolz H | Human mutation | 2004 | PMID: 15300860 |
Text-mined citations for rs2135473615 ...
HelpThese 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
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.