VCV000560897.10 - ClinVar

NM_000260.4(MYO7A):c.3364C>A (p.Leu1122Ile)

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.

(6)

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
Uncertain significance(3); 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_000260.4(MYO7A):c.3364C>A (p.Leu1122Ile)

Variation ID: 560897 Accession: VCV000560897.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q13.5 11: 76894191 (GRCh37) [ NCBI UCSC ] 11: 77183146 (GRCh38) [ 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	Sep 15, 2018	Nov 30, 2024	Nov 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000260.4:c.3364C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000251.3:p.Leu1122Ile	missense
NM_001127180.2:c.3364C>A	NP_001120652.1:p.Leu1122Ile	missense
NM_001369365.1:c.3331C>A	NP_001356294.1:p.Leu1111Ile	missense
NC_000011.10:g.77183146C>A
NC_000011.9:g.76894191C>A
NG_009086.2:g.59901C>A
LRG_1420:g.59901C>A
LRG_1420t1:c.3364C>A	LRG_1420p1:p.Leu1122Ile

... more HGVS ... less HGVS

Protein change

L1122I, L1111I

Other names

Canonical SPDI

NC_000011.10:77183145: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.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00015

Trans-Omics for Precision Medicine (TOPMed) 0.00015

The Genome Aggregation Database (gnomAD) 0.00016

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00017

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD), exomes 0.00004

1000 Genomes Project 30x 0.00031

Links

dbSNP: rs192378817 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	4353	4364

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.
Deafness	Pathogenic (1)	no assertion criteria provided	Sep 10, 2018	RCV000679824.2
Hearing loss, autosomal recessive	Likely pathogenic (1)	no assertion criteria provided	-	RCV001291474.1
Autosomal dominant nonsyndromic hearing loss 11 Autosomal recessive nonsyndromic hearing loss 2 Usher syndrome type 1	Uncertain significance (1)	criteria provided, single submitter	Mar 3, 2022	RCV002485569.1
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Nov 18, 2024	RCV001771924.7
not specified	Uncertain significance (1)	criteria provided, single submitter	May 9, 2023	RCV003235344.1

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 (Mar 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 1 Autosomal recessive nonsyndromic hearing loss 2 Autosomal dominant nonsyndromic hearing loss 11 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002783380.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (May 09, 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: SCV003934401.1 First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023	Publications: PubMed (2) PubMed: 30303587‚ 36147510 Comment: Variant summary: MYO7A c.3364C>A (p.Leu1122Ile) results in a conservative amino acid change located in the MyTH4 domain (IPR000857) of the encoded protein sequence. Four of … (more) Variant summary: MYO7A c.3364C>A (p.Leu1122Ile) results in a conservative amino acid change located in the MyTH4 domain (IPR000857) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 155582 control chromosomes (gnomAD). c.3364C>A has been reported in the literature in the compound heterozygous state in two siblings affected with hearing loss and the variant was observed to segregate with the phenotype in an autosomal recessive inhertiance pattern in the family (Richard_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36147510, 30303587). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=3), or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
Likely benign (Nov 17, 2023)	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: SCV003522349.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024
Uncertain significance (Nov 18, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001992464.4 First in ClinVar: Nov 06, 2021 Last updated: Nov 30, 2024	Comment: Reported with a second variant in a family with autosomal recessive hearing loss in published literature, however, clinical information was not provided (PMID: 30303587); In … (more) Reported with a second variant in a family with autosomal recessive hearing loss in published literature, however, clinical information was not provided (PMID: 30303587); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 30303587, 36147510) (less)
Pathogenic (Sep 10, 2018)	no assertion criteria provided Method: research	Deafness Affected status: yes Allele origin: inherited	Center for Statistical Genetics, Columbia University Accession: SCV000804815.1 First in ClinVar: Sep 15, 2018 Last updated: Sep 15, 2018 Comment: Autosomal recessive
Likely pathogenic (-)	no assertion criteria provided Method: research	non-syndromic autosomal recessive hearing loss Affected status: yes Allele origin: inherited	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV001479978.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Publications: PubMed (1) PubMed: 30303587

Comment:

Variant summary: MYO7A c.3364C>A (p.Leu1122Ile) results in a conservative amino acid change located in the MyTH4 domain (IPR000857) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 155582 control chromosomes (gnomAD). c.3364C>A has been reported in the literature in the compound heterozygous state in two siblings affected with hearing loss and the variant was observed to segregate with the phenotype in an autosomal recessive inhertiance pattern in the family (Richard_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36147510, 30303587). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=3), or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Comment:

Reported with a second variant in a family with autosomal recessive hearing loss in published literature, however, clinical information was not provided (PMID: 30303587); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 30303587, 36147510)

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
Genomic study of nonsyndromic hearing loss in unaffected individuals: Frequency of pathogenic and likely pathogenic variants in a Brazilian cohort of 2,097 genomes.	Quaio CRAC	Frontiers in genetics	2022	PMID: 36147510
Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss.	Richard EM	Human mutation	2019	PMID: 30303587

Text-mined citations for rs192378817 ...

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 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000260.4(MYO7A):c.3364C>A (p.Leu1122Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs192378817 ...