Submissions for variant NM_000394.4(CRYAA):c.347G>A (p.Arg116His)

dbSNP: rs121912973

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483566	SCV000567114	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with loss of chaperone activity (Gu et al., 2008; Kore et al., 2012); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31628766, 34169787, 22140512, 20079887, 18302245, 17724170, 22045060, 30078984, 18407550, 22216983)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000059327	SCV000833565	pathogenic	Cataract 9 multiple types	2022-07-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg116 amino acid residue in CRYAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9467006, 10684623, 11123904, 16735993, 17296897, 18085469, 22045060). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects CRYAA function (PMID: 20079887, 22045060, 22140512). 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 expected to disrupt CRYAA protein function. ClinVar contains an entry for this variant (Variation ID: 16960). This missense change has been observed in individual(s) with autosomal dominant congenital cataract (PMID: 17724170, 18302245, 22216983). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 116 of the CRYAA protein (p.Arg116His).
OMIM	RCV000018473	SCV000038755	pathogenic	Cataract 9, multiple types, with microcornea	2008-04-01	no assertion criteria provided	literature only
OMIM	RCV000059327	SCV000105905	pathogenic	Cataract 9 multiple types	2007-09-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004730849	SCV005340171	pathogenic	CRYAA-related disorder	2024-06-20	no assertion criteria provided	clinical testing	The CRYAA c.347G>A variant is predicted to result in the amino acid substitution p.Arg116His. This variant has been reported to co-segregate with disease in multiple individuals from a large family with cataracts (Figure 1, Hansen et al. 2007. PubMed ID: 17724170). This variant has not been reported in a large population database, indicating it is rare. In vitro experimental studies suggest this variant decreases chaperone activity and leads to intracellular aggregation (Figure 9, Kore et al. 2011. PubMed ID: 22045060; Figure 1, Raju et al. 2011. PubMed ID: 22140512). A different missense change affecting the same amino acid (p.Arg116Cys) has been reported to co-segregate with disease in multiple families with cataracts (Figure 1, Litt et al. 1998. PubMed ID: 9467006; Figure 1, Vanita et al. 2006. PubMed ID: 16735993; Figure 2, Beby et al. 2007. PubMed ID: 17296897). Given the evidence, the c.347G>A (p.Arg116His) variant is interpreted as pathogenic.