Submissions for variant NM_000260.4(MYO7A):c.3476G>T (p.Gly1159Val)

gnomAD frequency: 0.00021  dbSNP: rs199897298

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036110	SCV000059762	likely pathogenic	Rare genetic deafness	2016-10-13	criteria provided, single submitter	clinical testing	The p.Gly1159Val variant in MYO7A has been reported in 9 individuals with hearin g loss (Roux 2011, Schrauwen 2013, LMM data). Four of these individuals were co mpound heterozygous with a second pathogenic or likely pathogenic MYO7A variant, with no indication of retinitis pigmentosa associated with Usher syndrome. Anot her with retinitis pigmentosa had a second variant of uncertain significance in MYO7A. This individual also reportedly has LCHAD, which may explain the retiniti s pigmentosa. This variant has been identified in 12/30732 (0.04%) of European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs199897298); however, this frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conserva tion analysis suggest that this variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In summary, althoug h additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hearing loss. However, it cannot be determined whether this variant causes type 1 Usher syndrome, atyp ical Usher syndrome, or nonsyndromic hearing loss without additional information .
GeneDx	RCV000312187	SCV000329830	pathogenic	not provided	2024-06-06	criteria provided, single submitter	clinical testing	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: 26486028, 31589614, 31964843, 26969326, 23208854, 27068579, 21436283, 30245029, 27160483, 32795431, 36515421, 35885997)
Eurofins Ntd Llc (ga)	RCV000312187	SCV000705705	pathogenic	not provided	2017-02-09	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001073977	SCV001239543	likely pathogenic	Retinal dystrophy	2018-09-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000312187	SCV001419975	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1159 of the MYO7A protein (p.Gly1159Val). This variant is present in population databases (rs199897298, gnomAD 0.05%). This missense change has been observed in individual(s) with autosomal recessive nonsyndromic deafness or Usher syndrome (PMID: 21436283, 23208854, 26969326, 27068579). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1019G>T (p.Gly340Val). ClinVar contains an entry for this variant (Variation ID: 43206). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001270103	SCV001448929	likely pathogenic	Hearing loss	2019-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496550	SCV002807600	pathogenic	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2021-09-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000312187	SCV004010103	likely pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	MYO7A: PM3:Strong, PM1, PM2, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004541086	SCV005040812	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-03-01	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3476G>T (p.Trp1159Leu) results in a non-conservative amino acid change located in the WD40 domain (IPR031920) of 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 251480 control chromosomes (gnomAD v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3476G>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function and found no damaging effect of this variant on homologous recombination or in a PARP inhibitor sensitivity assay (e.g., Boonen_2019). The following publication was ascertained in the context of this evaluation (PMID: 31757951). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004579535	SCV005062120	likely pathogenic	MYO7A-related disorder	2024-03-01	criteria provided, single submitter	clinical testing	Variant summary: MYO7A c.3476G>T (p.Gly1159Val) results in a non-conservative amino acid change located in the MyTH4 domain (IPR000857) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 224146 control chromosomes, allowing no conclusion about variant significance. c.3476G>T has been reported in the literature in the compound heterozygous state in multiple individuals affected with autosomal recessive non-syndromic hearing loss (e.g. Roux_2011, Schrauwen_2013, Sloan-Heggen_2016, Sommen_2016, Zazo-Seco_2017, van Beeck Calkoen_2019) and in at least one compound heterozygous individual with retinitis pigmentosa (Georgiou_2021). These data indicate that the variant is likely to 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: 32795431, 21436283, 23208854, 26969326, 27068579, 28000701, 31152317). ClinVar contains an entry for this variant (Variation ID: 43206). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000664879	SCV005400209	pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness autosomal dominant 11 (MIM#601317), deafness autosomal recessive 2 (MIM#600060) and Usher syndrome, type 1B (MIM#276900). In addition, dominant negative is the suggested mechanism for missense variants in autosomal dominant inheritance (OMIM, PMID: 23383098). (I) 0108 - This gene is associated with both recessive and dominant disease. While the genotype-phenotype correlation is unestablished, missense variants causing autosomal dominant inheritance are rare and are not localised to a specific protein region (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (58 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated MyTH4 domain (DECIPHER). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. This alternative change (p.(Gly1159Ser)) has been reported as a VUS (ClinVar) and as pathogenic (deafnessvariationdatabase.org), and has been observed in an individual with hearing loss (PMID: 25587757). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic and likely pathogenic, and observed in multiple compound heterozygous individuals with deafness, Usher syndrome and/or retinitis pigmentosa (ClinVar, deafnessvariationdatabase.org, PMID: 32795431, PMID: 31152317). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Counsyl	RCV000664879	SCV000788903	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2017-01-04	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001272512	SCV001454584	likely pathogenic	Usher syndrome type 1B	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000312187	SCV001951762	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000312187	SCV001976217	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000664879	SCV004099485	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2023-10-30	no assertion criteria provided	clinical testing