Submissions for variant NM_153700.2(STRC):c.4171C>G (p.Arg1391Gly)

dbSNP: rs376104748

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151950	SCV000200483	likely pathogenic	Rare genetic deafness	2020-01-10	criteria provided, single submitter	clinical testing	The p.Arg1391Gly variant in STRC has been reported in two Ashkenazi Jewish families with mild to moderate sensorineural hearing loss (Francey 2011). In one family, this variant was found in the homozygous state in all six affected siblings while unaffected parents were heterozygous for this variant. In the other family, the two affected siblings were compound heterozygous for the Arg1391Gly variant and a large deletion of the STRC gene. This variant has also been detected in 0.5% (1/182) of Ashkenazi Jewish control chromosomes by the same study (Francey 2011) and in 0.2% (20/9068) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). In summary, although additional studies are required to fully establish its clinical significance, this variant is classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM3, PP1_Strong, BS1_Supporting.
GeneDx	RCV000494575	SCV000582279	uncertain significance	not provided	2023-12-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 22147502)
Genome-Nilou Lab	RCV002467597	SCV002762988	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 16		criteria provided, single submitter	clinical testing
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV002467597	SCV004037365	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 16	2021-01-07	criteria provided, single submitter	clinical testing	The c.4171C>G variant in the STRC gene is missense variant, which results in the substitution of an arginine residue at amino acid position 1391 for a glycine (NP_116023.2). This variant localizes to coding exon 21 of the STRC gene (29 coding exons in total; NM_032634.4). In silico predictors for this variant are not consistent: It is predicted to be neutral to protein structure and/or function by PROVEAN, but is predicted to be damaging by SIFT. This variant was reported in Genome Aggregation Database (gnomAD) with an allelic frequency of 0.0129% (25 out of 193,244 alleles). This variant is reported in ClinVar as pathogenic/likely pathogenic by three laboratories (allele ID# 165311, last accessed 8/11/2020). This variant has been reported in two Ashkenazi Jewish families with mild to moderate hearing loss: in one family, the variant was found in the homozygous state in all six affected siblings while parents were heterozygous carriers. In the second family, two affected siblings were compound heterozygous for this variant and a large deletion of the STRC gene (PMID: 22147502). Given this evidence, the c.4171C>G (p.Arg1391Gly) variant in STRC is considered likely pathogenic. Parental studies were not conducted at our laboratory, but this variant was reported to be paternally-inherited in an older sibling
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398799	SCV004122714	pathogenic	Nonsyndromic genetic hearing loss	2023-10-10	criteria provided, single submitter	clinical testing	Variant summary: STRC c.4171C>G (p.Arg1391Gly) 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 allele was found at a frequency of 0.00013 in 193244 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in STRC causing Nonsyndromic Hearing Loss And Deafness, Type 16 (0.00013 vs 0.0011), allowing no conclusion about variant significance. c.4171C>G has been reported in the literature in multiple individuals affected with Nonsyndromic Hearing Loss And Deafness (Francey_2012, Sloan-Heggen_2016) and observed to segregate with disease. These data indicate that the variant is very 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: 22147502, 26969326). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000494575	SCV004225751	likely pathogenic	not provided	2022-02-25	criteria provided, single submitter	clinical testing	PM2, PM3_strong
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV000225023	SCV000282018	pathogenic	Autosomal dominant nonsyndromic hearing loss 16	2016-02-19	no assertion criteria provided	research	Congenital, mild-moderate HL