Submissions for variant NM_002775.5(HTRA1):c.958G>A (p.Asp320Asn)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282856	SCV002570729	pathogenic	Age related macular degeneration 7	2022-07-27	criteria provided, single submitter	clinical testing	Variant summary: HTRA1 c.958G>A (p.Asp320Asn) results in a conservative amino acid change located in the protease domain (Malik_2021) of 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 1.6e-05 in 250558 control chromosomes (gnomAD). The variant, c.958G>A, has been reported in the literature in heterozygous and compound heterozygous state in individuals affected with cerebral small vessel arteriopathy and/or diffuse leukoencephalopathy (e.g. Xie_2018, Tan_2019, Malik_2021, Muthusamy_2021), where individuals who carried the variant in heterozygous state, generally had a milder phenotype, without family history of the disease, which might indicate a reduced penetrance. These data indicate that the variant may be associated with disease. One of these publications also reported experimental evidence evaluating an impact on protein function, and found that the variant abolished serine protease activity (Malik_2021). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV003325599	SCV004031764	uncertain significance	not provided	2023-08-29	criteria provided, single submitter	clinical testing	Reported previously in an individual with CARASIL who harbored a second HRTA1 variant, however parental test results were not reported. The unaffected brother harbors the D320N variant (Xie et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34626176, 34510819, 30068478, 31719132)
PreventionGenetics, part of Exact Sciences	RCV003943344	SCV004771079	uncertain significance	HTRA1-related disorder	2024-02-15	no assertion criteria provided	clinical testing	The HTRA1 c.958G>A variant is predicted to result in the amino acid substitution p.Asp320Asn. This variant has been reported in the heterozygous state or compound heterozygous state in several individuals with cerebral small vessel disease (Xie and Zhang 2018. PubMed ID: 30068478; Tan et al. 2019. PubMed ID: 31719132; Muthusamy et al. 2021. PubMed ID: 34510819; Malik et al. 2021. PubMed ID: 34626176). In vitro functional studies have shown that this variant results in a loss of serine protease function (Malik et al. 2021. PubMed ID: 34626176). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. This variant is classified as pathogenic to uncertain significance in the ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/1704529/). Although we suspect that this variant may be pathogenic, the clinical significance of this variant is uncertain at this time due to the absence of conclusive functional and genetic evidence.