Submissions for variant NM_153700.2(STRC):c.4917_4918delinsCT (p.Leu1640Phe)

dbSNP: rs727503441

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151940	SCV000200473	uncertain significance	not specified	2019-10-11	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Leu1640Phe variant in STRC has been previously reported in 9 individuals with hearing loss, 7 of whom were compound heterozygous for a second pathogenic STRC variant (Mandelker 2014, Vona 2016, LMM unpublished data). One individual was homozygous for this variant, but a different nonsense variant was also identified in the homozygous state in this individual, indicating that the variants were in cis (LMM unpublished data). This variant has also been identified in 0.2% (256/128964) of European chromosomes (including 5 homozygotes) by the Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org/; dbSNP rs2860666 and rs2920791). Please note that the Genome Aggregation Database has listed this variant as two separate single nucleotide variants (see rs2860666 and rs2920791) but it was confirmed that the variants occur on the same allele in individuals reported in this database, which is consistent with the variant and amino acid change reported here. Computational prediction tools and conservation analysis suggest that the p.Leu1640Phe variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain due to its relative high frequency in the general population database, including 5 individuals who were homozygous. ACMG/AMP Criteria applied: BS1_Supporting, PM3, BP2.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000185573	SCV001745840	pathogenic	Autosomal recessive nonsyndromic hearing loss 16	2019-04-03	criteria provided, single submitter	clinical testing	This patient harbours a compound heterozygous CKMT1B, STRC,CATSPER2 deletion and a pathogenic variant in STRC
GeneDx	RCV001575950	SCV001803044	uncertain significance	not provided	2023-08-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25157971, 26011646, 30245029, 29907799, 36086952, 24963352, 30531641, 34440452, 36190904, 36979683)
Ambry Genetics	RCV002516055	SCV003656783	likely pathogenic	Inborn genetic diseases	2022-12-19	criteria provided, single submitter	clinical testing	The c.4917_4918delACinsCT (p.L1640F) alteration, located in exon 26 (coding exon 26) of the STRC gene, consists of an in-frame substitution of 2 nucleotides from position 4917 to 4918, causing the leucine (L) at amino acid position 1640 to be replaced by a phenylalanine (F). Based on data from gnomAD, the CT allele has an overall frequency of 0.117% (331/282340) total alleles studied. The highest observed frequency was 0.199% (256/128964) of European (non-Finnish) alleles. Allele frequencies in general population databases may be unreliable due to high homology with the STRCP1 pseudogene (Vona, 2015; Mandelker, 2014; Francey, 2012). This variant has been observed in trans with a second STRC pathogenic variant in multiple individuals with congenital hearing loss (Back, 2019; Sheppard, 2018; Vona, 2015; Mandelker, 2014). In addition, this variant has been observed as part of a pathogenic gene conversion event in trans with a second STRC variant in one individual with congenital bilateral sensorineural hearing loss (Conlin, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000185573	SCV000238473	uncertain significance	Autosomal recessive nonsyndromic hearing loss 16	2015-05-23	no assertion criteria provided	research	The heterozygous variant was identified in the STRC gene (c.4917_4918delinsCT; p.Leu1640Phe) is considered a variant of uncertain significance. This variant affects a highly conserved amino acid and has been previously published in 3 affected individuals (PMID: 2157971). This variant is also present in 131 alleles in the ExAC database, out of 121110 total alleles sequenced at this position.