VCV000043217.10 - ClinVar

NC_000011.10:g.77190085_77190095del

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.

(3)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000011.10:g.77190085_77190095del

Variation ID: 43217 Accession: VCV000043217.10

Type and length

Deletion, 11 bp

Location

Cytogenetic: 11q13.5 11: 77190084-77190094 (GRCh38) [ NCBI UCSC ] 11: 76901130-76901140 (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 30, 2015	Feb 14, 2024	Oct 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000260.4:c.3696_3706del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000251.3:p.Arg1232fs
NM_001127180.2:c.3696_3706del	NP_001120652.1:p.Arg1232fs
NM_001369365.1:c.3663_3673del	NP_001356294.1:p.Arg1221fs
NC_000011.10:g.77190085_77190095del
NC_000011.9:g.76901130_76901140del
NG_009086.2:g.66840_66850del
LRG_1420:g.66840_66850del
LRG_1420t1:c.3696_3706del	LRG_1420p1:p.Arg1232fs

... more HGVS ... less HGVS

Protein change

R1221fs, R1232fs

Other names

Canonical SPDI

NC_000011.10:77190083:GAAGGACCTTTG:G

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.

Links

ClinGen: CA278656 dbSNP: rs397516303 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.
Rare genetic deafness	Pathogenic (1)	criteria provided, single submitter	Apr 23, 2010	RCV000036121.5
Usher syndrome type 1B	Pathogenic (1)	no assertion criteria provided	Jul 14, 2020	RCV001826546.1
not provided	Pathogenic (1)	criteria provided, single submitter	Oct 13, 2023	RCV001852745.4

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 (Apr 23, 2010)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Rare genetic deafness Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059773.6 First in ClinVar: May 03, 2013 Last updated: Jan 30, 2015	Comment: The 3696_3706del (Arg1232fs) variant in MYO7A has not been reported in the liter ature nor previously identified by our laboratory. However, the Arg1232fs varian t … (more) The 3696_3706del (Arg1232fs) variant in MYO7A has not been reported in the liter ature nor previously identified by our laboratory. However, the Arg1232fs varian t is predicted to cause a frameshift, which alters the protein's amino acid sequ ence beginning at codon 1232 and leads to a premature stop codon 72 codons downs tream. This alteration is then predicted to lead to a truncated or absent protei n. In summary, this variant is highly likely to be pathogenic. (less) Number of individuals with the variant: 1
Pathogenic (Oct 13, 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: SCV002238557.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 8900236‚ 25404053‚ 28731162‚ 30029497 Comment: This sequence change creates a premature translational stop signal (p.Arg1232Serfs72) in the MYO7A gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg1232Serfs72) in the MYO7A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with autosomal recessive MYO7A-related conditions (PMID: 28731162, 30029497). ClinVar contains an entry for this variant (Variation ID: 43217). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 14, 2020)	no assertion criteria provided Method: clinical testing	Usher syndrome type 1B Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002086681.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Comment:

The 3696_3706del (Arg1232fs) variant in MYO7A has not been reported in the liter ature nor previously identified by our laboratory. However, the Arg1232fs varian t is predicted to cause a frameshift, which alters the protein's amino acid sequ ence beginning at codon 1232 and leads to a premature stop codon 72 codons downs tream. This alteration is then predicted to lead to a truncated or absent protei n. In summary, this variant is highly likely to be pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Arg1232Serfs*72) in the MYO7A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with autosomal recessive MYO7A-related conditions (PMID: 28731162, 30029497). ClinVar contains an entry for this variant (Variation ID: 43217). For these reasons, this variant has been 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Application of Whole Exome and Targeted Panel Sequencing in the Clinical Molecular Diagnosis of 319 Chinese Families with Inherited Retinal Dystrophy and Comparison Study.	Wang L	Genes	2018	PMID: 30029497
A homozygous MYO7A mutation associated to Usher syndrome and unilateral auditory neuropathy spectrum disorder.	Xia H	Molecular medicine reports	2017	PMID: 28731162
Targeted next generation sequencing for molecular diagnosis of Usher syndrome.	Aparisi MJ	Orphanet journal of rare diseases	2014	PMID: 25404053
Myosin VIIA mutation screening in 189 Usher syndrome type 1 patients.	Weston MD	American journal of human genetics	1996	PMID: 8900236

Text-mined citations for rs397516303 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NC_000011.10:g.77190085_77190095del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397516303 ...