rs727503441

Positions:

• chr15-43600609-GT-AG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_153700.2(STRC):​c.4917_4918delinsCT​(p.Leu1640Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1639L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 26)
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 2.79

Genes affected

STRC (HGNC:16035): (stereocilin) This gene encodes a protein that is associated with the hair bundle of the sensory hair cells in the inner ear. The hair bundle is composed of stiff microvilli called stereocilia and is involved with mechanoreception of sound waves. This gene is part of a tandem duplication on chromosome 15; the second copy is a pseudogene. Mutations in this gene cause autosomal recessive non-syndromic deafness. [provided by RefSeq, Jul 2008]

CKMT1B (HGNC:1995): (creatine kinase, mitochondrial 1B) Mitochondrial creatine (MtCK) kinase is responsible for the transfer of high energy phosphate from mitochondria to the cytosolic carrier, creatine. It belongs to the creatine kinase isoenzyme family. It exists as two isoenzymes, sarcomeric MtCK and ubiquitous MtCK, encoded by separate genes. Mitochondrial creatine kinase occurs in two different oligomeric forms: dimers and octamers, in contrast to the exclusively dimeric cytosolic creatine kinase isoenzymes. Many malignant cancers with poor prognosis have shown overexpression of ubiquitous mitochondrial creatine kinase; this may be related to high energy turnover and failure to eliminate cancer cells via apoptosis. Ubiquitous mitochondrial creatine kinase has 80% homology with the coding exons of sarcomeric mitochondrial creatine kinase. Two genes located near each other on chromosome 15 have been identified which encode identical mitochondrial creatine kinase proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-43600609-GT-AG is Pathogenic according to our data. Variant chr15-43600609-GT-AG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165301.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STRC	NM_153700.2	c.4917_4918delinsCT	p.Leu1640Phe	missense_variant	26/29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.4917_4918delinsCT	p.Leu1640Phe	missense_variant	26/29	5	NM_153700.2	ENSP00000401513	P2

Frequencies

GnomAD3 genomes Cov.: 26

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 16 Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	May 23, 2015	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Apr 03, 2019	This patient harbours a compound heterozygous CKMT1B, STRC,CATSPER2 deletion and a pathogenic variant in STRC -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 11, 2019

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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 24, 2023

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) -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503441; hg19: chr15-43892807;