VCV000016960.14 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 16960 Accession: VCV000016960.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q22.3 21: 43172105 (GRCh38) [ NCBI UCSC ] 21: 44592215 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 23, 2013	Oct 8, 2024	Dec 1, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000394.4:c.347G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000385.1:p.Arg116His	missense
NM_001363766.1:c.236G>A	NP_001350695.1:p.Arg79His	missense
NC_000021.9:g.43172105G>A
NC_000021.8:g.44592215G>A
NG_009823.1:g.8075G>A
	P02489:p.Arg116His

... more HGVS ... less HGVS

Protein change

R116H, R79H

Other names

Canonical SPDI

NC_000021.9:43172104:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA127002 UniProtKB: P02489#VAR_046893 OMIM: 123580.0004 OMIM: 123580.0007 dbSNP: rs121912973 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CRYAA		-	-	GRCh38 GRCh37	89	186

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cataract 9, multiple types, with microcornea	Pathogenic (1)	no assertion criteria provided	Apr 1, 2008	RCV000018473.32
Cataract 9 multiple types	Pathogenic (2)	criteria provided, single submitter	Jul 6, 2022	RCV000059327.29
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 1, 2022	RCV000483566.4
CRYAA-related disorder	Pathogenic (1)	no assertion criteria provided	Jun 20, 2024	RCV004730849.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jul 06, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cataract 9 multiple types Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000833565.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (13) PubMed: 28492532‚ 9467006‚ 10684623‚ 11123904‚ 16735993‚ 17296897‚ 18085469‚ 22045060‚ 20079887‚ 22140512‚ 17724170‚ 18302245‚ 22216983 Comment: 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 … (more) 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). (less)
Pathogenic (Dec 01, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000567114.7 First in ClinVar: Apr 27, 2017 Last updated: Dec 11, 2022	Comment: 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 … (more) 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) (less)
Pathogenic (Sep 01, 2007)	no assertion criteria provided Method: literature only	CATARACT 9, NUCLEAR, WITH MICROCORNEA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000105905.1 First in ClinVar: Oct 23, 2013 Last updated: Oct 23, 2013	Publications: PubMed (1) PubMed: 17724170 Comment on evidence: In 7 affected members over 3 generations of a Danish family segregating autosomal dominant congenital nuclear cataract with microcornea (CTRCT9; 604219), Hansen et al. (2007) … (more) In 7 affected members over 3 generations of a Danish family segregating autosomal dominant congenital nuclear cataract with microcornea (CTRCT9; 604219), Hansen et al. (2007) identified heterozygosity for a c.337G-A transition in the CRYAA gene, resulting in an arg116-to-his (R116H) substitution at 1 of the most highly conserved residues in the alpha-crystallin domain. The mutation was not found in 6 unaffected family members or 170 ethnically matched controls. Examination of affected family members revealed nuclear cataracts with polar and/or equatorial ramification; corneas were 8 to 10 mm in diameter. (less)
Pathogenic (Apr 01, 2008)	no assertion criteria provided Method: literature only	CATARACT 9, MULTIPLE TYPES, WITH MICROCORNEA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038755.6 First in ClinVar: Apr 04, 2013 Last updated: Sep 08, 2021	Publications: PubMed (2) PubMed: 16564818‚ 18302245 Comment on evidence: In 14 affected members of a large 4-generation Chilean family, previously reported by Shafie et al. (2006) as 'family ADC54,' segregating autosomal dominant cataract, microcornea, … (more) In 14 affected members of a large 4-generation Chilean family, previously reported by Shafie et al. (2006) as 'family ADC54,' segregating autosomal dominant cataract, microcornea, and/or corneal opacity (CTRCT9; 604219), Richter et al. (2008) identified a 414G-A transition in exon 3 of the CRYAA gene, resulting in an arg116-to-his (R116H) substitution that changes a positively charged residue to a slightly negatively charged residue in a highly conserved region. The mutation was not found in 12 controls. There was significant asymmetry of density, morphology, and color of the cataracts within and between affected individuals; the variable morphology included anterior polar, cortical, embryonal, fan-shaped, and anterior subcapsular cataracts. Microcornea was evident in 3 affected individuals. Richter et al. (2008) noted that other affected individuals with nystagmus might also have mild microcornea, which could only be measured under anesthesia. (less)
Pathogenic (Jun 20, 2024)	no assertion criteria provided Method: clinical testing	CRYAA-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005340171.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)

Comment:

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).

Comment:

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)

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Identification of the p. R116H mutation in a Chinese family with novel variable cataract phenotype: evidence for a mutational hot spot in αA-crystallin gene.	Wang B	Ophthalmic genetics	2012	PMID: 22216983
Quaternary structural parameters of the congenital cataract causing mutants of αA-crystallin.	Kore R	Molecular and cellular biochemistry	2012	PMID: 22045060
Congenital cataract causing mutants of αA-crystallin/sHSP form aggregates and aggresomes degraded through ubiquitin-proteasome pathway.	Raju I	PloS one	2011	PMID: 22140512
Effects of congenital cataract mutation R116H on alphaA-crystallin structure, function and stability.	Pang M	Biochimica et biophysica acta	2010	PMID: 20079887
Clinical variability of autosomal dominant cataract, microcornea and corneal opacity and novel mutation in the alpha A crystallin gene (CRYAA).	Richter L	American journal of medical genetics. Part A	2008	PMID: 18302245
Differential binding of mutant (R116C) and wildtype alphaA crystallin to actin.	Brown Z	Current eye research	2007	PMID: 18085469
Genetic heterogeneity in microcornea-cataract: five novel mutations in CRYAA, CRYGD, and GJA8.	Hansen L	Investigative ophthalmology & visual science	2007	PMID: 17724170
New phenotype associated with an Arg116Cys mutation in the CRYAA gene: nuclear cataract, iris coloboma, and microphthalmia.	Beby F	Archives of ophthalmology (Chicago, Ill. : 1960)	2007	PMID: 17296897
A novel fan-shaped cataract-microcornea syndrome caused by a mutation of CRYAA in an Indian family.	Vanita V	Molecular vision	2006	PMID: 16735993
Autosomal dominant cataract: intrafamilial phenotypic variability, interocular asymmetry, and variable progression in four Chilean families.	Shafie SM	American journal of ophthalmology	2006	PMID: 16564818
Structural and functional changes in the alpha A-crystallin R116C mutant in hereditary cataracts.	Cobb BA	Biochemistry	2000	PMID: 11123904
Mutation of R116C results in highly oligomerized alpha A-crystallin with modified structure and defective chaperone-like function.	Shroff NP	Biochemistry	2000	PMID: 10684623
Autosomal dominant congenital cataract associated with a missense mutation in the human alpha crystallin gene CRYAA.	Litt M	Human molecular genetics	1998	PMID: 9467006
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Text-mined citations for rs121912973 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121912973 ...