rs869312181

Positions:

• chr11-77192241-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3 PM5_Supporting PP3 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.4115T>G variant in MYO7A is a missense variant predicted to cause substitution of valine by glycine at amino acid 1372. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001332 (1/75054 alleles) in the African/African-American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.869, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). At least one patient with this variant displayed congenital sensorineural hearing loss, delayed gross motor development, and rod-cone dystrophy, which is highly specific for Usher syndrome (PP4, PMID:31836858). This individual was compound heterozygous for the variant and a pathogenic variant published by multiple submitters in ClinVar (c.6025del (p.Ala2009Profs*32)) and confirmed in trans by parental testing (1 PM3 point, PMID:31836858). A different missense variant in the same codon (c.4114G>A (p.Val1372Met), PMID:33576163), has been reported in the homozygous state in a patient with hearing loss and retinitis pigmentosa. However, this other variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Hearing loss VCEP (PM5_Supporting). In summary, this variant has been classified as a likely pathogenic variant for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PP3, PP4, PM2_Supporting, PM5_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 11/26/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA353603/MONDO:0019501/005

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.67

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

MYO7A (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.4115T>G	p.Val1372Gly	missense_variant	31/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.4115T>G	p.Val1372Gly	missense_variant	31/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.4115T>G	p.Val1372Gly	missense_variant	31/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4082T>G	p.Val1361Gly	missense_variant	32/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.1658T>G	p.Val553Gly	missense_variant	11/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.1955T>G		non_coding_transcript_exon_variant	14/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461688 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Usher syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Nov 26, 2024

The c.4115T>G variant in MYO7A is a missense variant predicted to cause substitution of valine by glycine at amino acid 1372. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001332 (1/75054 alleles) in the African/African-American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.869, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). At least one patient with this variant displayed congenital sensorineural hearing loss, delayed gross motor development, and rod-cone dystrophy, which is highly specific for Usher syndrome (PP4, PMID: 31836858). This individual was compound heterozygous for the variant and a pathogenic variant published by multiple submitters in ClinVar (c.6025del (p.Ala2009Profs*32)) and confirmed in trans by parental testing (1 PM3 point, PMID: 31836858). A different missense variant in the same codon (c.4114G>A (p.Val1372Met), PMID: 33576163), has been reported in the homozygous state in a patient with hearing loss and retinitis pigmentosa. However, this other variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Hearing loss VCEP (PM5_Supporting). In summary, this variant has been classified as a likely pathogenic variant for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PP3, PP4, PM2_Supporting, PM5_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 11/26/2024). -

Usher syndrome type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Jan 30, 2015

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 06, 2022

This variant disrupts the p.Val1372 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been observed in individuals with MYO7A-related conditions (PMID: 26872967, 31836858, 33576163), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 224749). This missense change has been observed in individual(s) with Usher syndrome (PMID: 26872967, 31836858). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1372 of the MYO7A protein (p.Val1372Gly). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Retinal dystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;.;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.5	M;M;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.4	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.96	D;.;.;.
Vest4		0.71
MutPred		0.56		Loss of stability (P = 0.009);Loss of stability (P = 0.009);.;.;
MVP		0.90
MPC		0.48
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.85
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.84		Position offset: -5
DS_DL_spliceai		0.22		Position offset: 37

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869312181; hg19: chr11-76903286;