Submissions for variant NM_006947.4(SRP72):c.133G>A (p.Val45Ile)

gnomAD frequency: 0.00006  dbSNP: rs201940585

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000266588	SCV000450159	benign	Autosomal dominant aplasia and myelodysplasia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Genetic Services Laboratory, University of Chicago	RCV001821063	SCV002064891	uncertain significance	not specified	2019-07-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001355587	SCV002220799	uncertain significance	not provided	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 45 of the SRP72 protein (p.Val45Ile). This variant is present in population databases (rs201940585, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SRP72-related conditions. ClinVar contains an entry for this variant (Variation ID: 349118). 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 not expected to disrupt SRP72 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003409552	SCV004111060	uncertain significance	SRP72-related disorder	2023-06-01	criteria provided, single submitter	clinical testing	The SRP72 c.133G>A variant is predicted to result in the amino acid substitution p.Val45Ile. To our knowledge, this variant has not been reported to be associated with disorders in the literature. This variant is reported in 0.018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-57335842-G-A) and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain significance (http://www.ncbi.nlm.nih.gov/clinvar/variation/349118). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355587	SCV001550513	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SRP72 p.Val45Ile variant was identified in dbSNP (ID: rs201940585) and ClinVar (classified as uncertain significance by Illumina). The variant was identified in control databases in 26 of 267648 chromosomes at a frequency of 0.00009714 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 21 of 117954 chromosomes (freq: 0.000178) and Latino in 5 of 34924 chromosomes (freq: 0.000143), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Val45 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. The p.V45I variant was found to disrupt the interaction between the SRP68 and SRP72 proteins (Gao_2017_PMID:28369529). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.