Submissions for variant NM_000441.2(SLC26A4):c.1265T>C (p.Val422Ala)

dbSNP: rs1057520369

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000417941	SCV000514665	likely pathogenic	not provided	2018-09-17	criteria provided, single submitter	clinical testing	The V422A variant in the SLC26A4 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, missense variants at this same codon (V422D and V422I) have been reported in the heterozygous state with a second pathogenic variant in individuals with SLC26A4-related disorders (Banghova et al., 2008; Zhao et al., 2014). Furthermore, missense variants in nearby residues (T420I, Q421K, Q421P, Q421R, Q421L, G424D, I426N) have been reported in the Human Gene Mutation Database in association with SLC26A4-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The V422A variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V422A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. The V422A variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Illumina Laboratory Services, Illumina	RCV001162714	SCV001324676	uncertain significance	Pendred syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001162715	SCV001324677	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731673	SCV001984734	uncertain significance	not specified	2020-02-25	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001162715	SCV002027195	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001162714	SCV002027206	uncertain significance	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV001162715	SCV002072987	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4		criteria provided, single submitter	clinical testing	The missense variant p.V422A in SLC26A4 (NM_000441.2) has been submitted to ClinVar with varying interpretations of Pathogenicity. Other missense variants affecting the same amino acid (V422D and V422I) have been reported to be disease causing. The V224A variant has not been reported in affected individuals in literature. The p.V422A variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.V422A missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1265 in SLC26A4 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.