rs121912973

Positions:

• chr21-43172105-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000394.4(CRYAA):​c.347G>A​(p.Arg116His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R116C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CRYAA NM_000394.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.10

Genes affected

CRYAA (HGNC:2388): (crystallin alpha A) Mammalian lens crystallins are divided into alpha, beta, and gamma families. Alpha crystallins are composed of two gene products: alpha-A and alpha-B, for acidic and basic, respectively. Alpha crystallins can be induced by heat shock and are members of the small heat shock protein (HSP20) family. They act as molecular chaperones although they do not renature proteins and release them in the fashion of a true chaperone; instead they hold them in large soluble aggregates. Post-translational modifications decrease the ability to chaperone. These heterogeneous aggregates consist of 30-40 subunits; the alpha-A and alpha-B subunits have a 3:1 ratio, respectively. Two additional functions of alpha crystallins are an autokinase activity and participation in the intracellular architecture. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Alpha-A and alpha-B gene products are differentially expressed; alpha-A is preferentially restricted to the lens and alpha-B is expressed widely in many tissues and organs. Defects in this gene cause autosomal dominant congenital cataract (ADCC). [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a chain Alpha-crystallin A(1-168) (size 167) in uniprot entity CRYAA_HUMAN there are 32 pathogenic changes around while only 0 benign (100%) in NM_000394.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43172104-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 21-43172105-G-A is Pathogenic according to our data. Variant chr21-43172105-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43172105-G-A is described in Lovd as [Pathogenic]. Variant chr21-43172105-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYAA	NM_000394.4	c.347G>A	p.Arg116His	missense_variant	3/3	ENST00000291554.6	NP_000385.1
CRYAA	NM_001363766.1	c.236G>A	p.Arg79His	missense_variant	3/3		NP_001350695.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYAA	ENST00000291554.6	c.347G>A	p.Arg116His	missense_variant	3/3	1	NM_000394.4	ENSP00000291554	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 9 multiple types Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2022	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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2007	- -

CRYAA-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2024

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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2022

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) -

Cataract 9, multiple types, with microcornea Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.92
MutPred		0.97		Loss of MoRF binding (P = 0.0844);.;.;
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.95
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121912973; hg19: chr21-44592215; COSMIC: COSV99374975;